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Transplant in the 21st century Kim Zuber, PA-C, DFAAPA; Tricia Howard, PA-C, MHS, DFAAPA; Jane Davis, DNP
ABSTRACT Organ transplantation has enriched and prolonged the lives of many patients who otherwise would have died of organ failure. Many of these advances, which occurred in the later part of the 20th century, are due to improved techniques and pharmacological management. Today, almost every organ can be transplanted. However, donor and recipient criteria can vary widely according to the organ(s) in question. This article reviews the historical changes that have occurred in transplant along with current criteria for donors and recipients, and describes the newest outreach to increase the donor pool. Keywords: transplant, living donation, deceased donor, organ, extended criteria, xenotransplantation
Learning objectives Discuss the historical changes that have occurred in transplant. Identify current criteria for organ donors and recipients. Describe the newest outreach to increase the donor pool.
M
ary Shelley’s 1831 novel, Frankenstein, told the story of a being created from organs and body parts of deceased humans. Modern organ transplantation takes viable organs from deceased or living donors to prolong life for those whose organs have been damaged by disease, trauma, or environmental factors. Shelley was not the first to dream of transplantation; the first recorded blood transfusion, from husband to wife after childbirth, occurred in 1818. The obstetrician, James Kim Zuber practices at Metropolitan Nephrology in Alexandria, Va., and is AAPA Outstanding PA of the Year. Tricia Howard is director of preclinical education at South University in Savannah, Ga., and chair of the National Kidney Foundation’s council of advanced practitioners. Jane Davis is a nurse practitioner at the University of Alabama at Birmingham and a member of the National Kidney Foundation’s board of directors and the American Society of Nephrology’s CME committee. The authors have disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000455644.58683.e8 Copyright © 2014 American Academy of Physician Assistants
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Blundell, transfused 10 women with their husbands’ blood and saved half of them.1 The 20th century was the golden age of transplantation. Kidneys and corneas have led the way and most organs are now transplanted. A notable exception is the brain, which interestingly was the downfall of Shelley’s creation. The 1984 National Organ Transplant Act established a central registry linking donors and potential recipients along with a registry of organ recipients run by the United Network of Organ Sharing (UNOS, http://unos.org). The act also authorized the Organ Procurement and Transplantation Network (OPTN, http://optn.transplant.hrsa.gov/data/ default.asp), which is responsible for the development of US transplant policies and publication of an annual report on the scientific and clinical status of organ transplantation. Much of the data used for this article are available on the UNOS and OPTN websites. We encourage any interested physician assistants (PAs) to log onto these websites for updated information for patients and families. This overview of organ transplantation is to educate PAs on transplant changes for the 21st century; management of the posttransplant patient is beyond the scope of this article. The United States is divided into 11 donation service areas. When an organ is recovered from a deceased donor, it is offered within the donation service area; if no match is found locally, the offer is made nationwide through the UNet system, which electronically links all transplant Volume 27 • Number 11 • November 2014
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Key points Organ transplantation has become commonplace, and PAs in primary care should be familiar with types of transplants and protocols so that they can provide care for posttransplant patients. Kidneys are the most frequently transplanted organ and have the longest list waiting time. Medications for transplant patients should be adjusted based on the patient’s estimated glomerular filtration rate. Because of the shortage of donor organs, PAs should encourage patients to consider donation and help dispel misconceptions about organ donation.
hospitals in a secure, real-time environment using the Internet.2 This local, then national, allocation system was originally developed to decrease organ cold ischemic time. Although kidneys continue to be the most frequently transplanted organ with the longest list waiting time, length of waiting time differs in each donation service area (Figure 1). In two instances, this system is bypassed: if there is a perfect match (0 mismatch) of the six human leukocyte antigens (HLAs) or if the recipient is a previous organ donor. All previous organ donors are automatically placed on the top of the transplant list as payback for having previously donated.3 More than 121,000 patients were on transplant waiting lists as of January 1, 2014.2 The vast majority, 96,922, were waiting for a kidney; 15,818 patients were on the liver transplant list (Figure 2). Organs can be recovered from deceased or living donors. Donation after circulatory death (DCD) is also commonly referred to as donation after cardiac death. The newest category, extended criteria donor (ECD), has expanded the resource pool. This is also referred to as extended donor criteria in some publications but we will use the UNOS designation in this article. What defines an ECD organ is specific to the type of transplant. These extended criteria were developed to decrease waste of viable organs with the knowledge that transplant increases survival for patients within any organ system. Each type of donation—deceased donor, living donor, ECD, and DCD—will be discussed by organ and listing protocols will be reviewed. Pediatric donations have their own criteria and are beyond the scope of this article. KIDNEY The kidney is the most commonly transplanted organ in the United States. The first successful kidney transplant occurred
FIGURE 1. Variation in waiting time (months) for patients
receiving a deceased donor kidney in 2011, by donation service area
in Boston on December 23, 1954. Ronald Herrick donated a kidney to his identical twin brother, Richard, who was dying from chronic nephritis. The 5.5-hour surgery was performed by Joseph Murray, MD, a plastic surgeon.4 Richard’s life was saved by the successful surgery, and he later married his recovery room nurse. They had two children, one of whom is a dialysis nurse. Richard died in 1962 after his chronic nephritis returned.5 Kidney transplantation is now the preferred therapeutic modality for patients with kidney disease.6 Nearly 97,000 patients were on the kidney transplant waiting list as of January 1, 2014. Of those, 20% are likely to receive a transplant within a year and about 6% of the patients on the waiting list will die.7 Kidneys have the longest waiting time of any transplanted organ—the average can be as long as 8 years in some regions of the United States—so efforts are under way to increase donations (Figure 3). Donations may be from living or deceased
FIGURE 2. US waiting list additions, 2003-2012
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donors. In 2011, about 5,770 living donor transplants were performed.8 A living kidney donor need not be related to the recipient, but must pass an extensive medical workup. A deceased donor kidney may be recovered from a standard criteria donor (SCD), ECD, DCD, or after brain death. Rates of organ recovery and transplant are different in each donation service area, with some transplant centers more likely to transplant an ECD or DCD organ (Figures 4 and 5). The Uniform Anatomical Gift Act lets a person or family give permission to donate any organs.9 “Domino” transplants can be used to increase the number of transplants for recipients who have a nonmatching donor.10 By using a system that trades kidneys between donors and recipients nationwide, with or without an altruistic donor in the chain, a domino-effect transplant chain can be
created. This lets more patients have living donor transplants, the preferred type of kidney transplant.6 Deceased donor kidneys are assessed based on several factors, including age, ethnicity, history of hypertension or diabetes, HLA antibodies, blood type, and serum creatinine. An ECD kidney is defined by age and/or comorbidities and offered to all recipients with emphasis on the older kidney patient. For kidneys, ECD donation is defined as: • donors over age 60 years • donors ages 50 to 59 years with one or more of the following: stroke as cause of death, history of hypertension, or serum creatinine greater than 1.5 mg/dL at time of death. As of July 2014, the ECD/SCD system has been fully replaced by the kidney donor profile index (KDPI) for all kidney transplants in adults.7 The deceased donor kidney is assigned a KDPI that rates kidney quality from highest to lowest projected longevity. The lower the percentage, the longer the expected life of the kidney.7 This percentage is then used to allocate donor kidneys to recipients based on the recipients’ projected life expectancy as calculated with age, comorbidities, and time on dialysis.11 The recipients with the highest life expectancy receive the higher-survival KDPI-scored donors and vice versa. Providers may access the KDPI at the OPTN website to review factors used to rank deceased donor kidneys. The recent passage of the HOPE (HIV Organ Policy Equity) act lets HIV-positive donors donate to HIV-positive recipients.12 Previously, HIV-positive donors could not donate, even if the recipient was HIV-positive. Patients with hepatitis B and C are listed for kidney transplants and are offered hepatitis-positive organs.6 Recipients who receive kidneys from live donors have longer graft survival than those patients receiving kidneys from deceased donors. The 10-year graft survival rate is 57% for recipients of
FIGURE 4. Organs recovered per donor, by donation status
FIGURE 5. Organs transplanted per donor, by donation status
FIGURE 3. Variation in the use of ECDs for kidney transplant
patients in 2011, by donation service area
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Transplant in the 21st century
living donor kidneys versus 41% for those who received kidneys from deceased donors.8 Acute postoperative complications of kidney transplant (whether living or deceased donor) include urine leaks, ureteral obstruction, vascular complications, and delayed graft function. Urine leak is the most common technical complication following transplant, occurring in 9.3% of patients; delayed graft function is the most common acute complication.6 Delayed graft function, which occurs in 21.3% of posttransplant patients, has several definitions but most often is defined as the use of dialysis within 7 days of transplant. Factors that place the recipient at risk for complications include obesity, diabetes, age over 55 years, male sex, and African American race. Once other causes of kidney dysfunction are excluded, patients should undergo kidney biopsy to assess for acute rejection. Studies have shown that delayed graft function does not have a negative effect on long-term graft survival.6 The ultimate complication is acute rejection. Induction therapy uses strong antirejection medications such as thymogloblin, alemtuzumab, and basiliximab and follows a transplant center–specific protocol peritransplant to decrease T-mediated cell proliferation and organ rejection.13 Despite the use of induction therapy and immunosuppressive agents, acute rejection still can occur; however, the incidence has been decreasing, and fewer than 15% of posttransplant patients develop acute rejection.6 Suspect organ rejection if the patient’s creatinine is rising. A kidney biopsy confirms the diagnosis. Recurrent disease may also occur at any time posttransplant, causing renal graft failure. The most frequent causes of recurrent renal disease are focal segmental glomerulosclerosis (20% to 50% of cases), IgA nephropathy (13% to 53%), lupus nephritis, membranous glomerulonephritis, and diabetic nephropathy.6 However, despite the potential complications, kidney transplantation becomes more successful each year, and can benefit many patients. LIVER In 1963, the first liver transplant was performed by Dr. Thomas Starzl at the University of Colorado. The recipient was Bernie Solis, a 3-year-old dying of biliary atresia.14 Unfortunately, Bernie died in surgery due to portal vein and clotting issues. Dr. Starzl’s first successful liver transplant was later that year, although the patient only lived 22 days posttransplant. The clotting difficulties with the intraoperative external bypass posed the main obstacle to successful and commonplace liver transplants. Alcohol abuse is the most frequent cause of adult liver failure, and a patient who is consuming alcohol cannot be placed on the active transplant waiting list.15 Patients whose alcohol abuse has caused liver failure cannot get a new liver if they are actively drinking. The restrictions depend on the transplant center, but usually patients must abstain from alcohol for 1 to 3 years. JAAPA Journal of the American Academy of Physician Assistants
In the United States, the most common diagnosis for patients on the liver transplant waiting list is hepatitis C, followed by acetaminophen toxicity and medicationinduced liver failure.16,17 Inclusion and priority on the liver transplant list is calculated by Model for End Stage Liver (MELD) score or Pediatric End State Liver (PELD) score; pediatric is defined as a patient under age 12 years.18 The MELD/PELD scores include specific hard data (dialysis two times in the last week, serum creatinine, bilirubin, and international normalized ratio) and are scored from 6 to 40.19 Although dialysis will move a patient up on the liver transplant list with a higher MELD score, few patients in need of a liver transplant are on dialysis. A higher score lets a patient receive a transplant sooner. Recently, controversy has arisen as to whether the sickest patients may be too sick to benefit from a liver transplant. However, OPTN does not plan to change the liver scoring for 2014.20 Liver transplants can be obtained from deceased or living donors. The right lobe of the liver is transplanted from a living donor to the recipient. In a deceased donor, the liver may be split at the time of procurement into two lobes, or the entire liver may be transplanted into one recipient. If the liver is split, the smaller lobe is often transplanted into a child.21 Extended criteria donor livers also are transplanted (Figure 6).22 For liver transplants, ECD is defined as: • donors ages 70 to 80 years • donors older than age 60 years with a significant medical history • donors with a history of high-risk social behaviors • donors with a history of hepatitis B or C exposure. HEART Hearts are the third most often transplanted organ. Dr. Christiaan Barnard performed the first heart transplant
FIGURE 6. Variations in the use of ECDs for patients receiving
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in 1967 in South Africa. The recipient, Louis Washkansky, died 22 days after the transplant due to pneumonia from immune system oversuppression secondary to antirejection drugs.23 Although heart failure continues to be the main cause of cardiac death, many patients with heart failure are too old or too sick to undergo a heart transplant. The most common causes of listing patients for a heart transplant are cardiomyopathy, congenital heart disease, and ischemic and/or valvular heart disease.24 Heart transplants from deceased donors can be a single organ, or part of a combination heart/lung transplant. Transplants can be single (native heart removed and donor heart placed), heterotopic (native heart is not removed and donor heart placed), or part of a domino heart transplant. A domino heart transplant occurs when a patient needing a lung transplant undergoes a heart/lung transplant. This patient’s native heart is then transplanted into a second recipient in a domino fashion.25 The development of heart devices has revolutionized heart transplants.26,27 Dr. Denton Cooley implanted the first artificial heart at the Texas Heart Institute in 1969; today, vascular assist devices (VADs) developed as bridges to heart transplantation are the more common approach. Willem Johan Kolff (the father of the first dialysis machine) developed the first VADs in the 1970s. The Jarvik 7, developed at the University of Utah in the Kolff laboratory, was the first implantable artificial heart pump designed for long-term use. Intra-aortic balloon pumps (IABPs) and extracorporeal membrane oxygenation (ECMO) are also common bridges to heart transplantation.28,29 Having a VAD or being on ECMO or an IABP will move a patient higher on the transplant list.20 A patient with a VAD (right, left, or bivalve) no longer must wait in the hospital for a heart transplant. Although a heart assist device will classify a patient as a higher priority for transplantation, hospitalization has been dropped from the priority rankings.30 Patients who do not have heart assist devices remain at lower priority on the transplant list.
TABLE 1.
Patients awaiting transplants as of January 1, 2014.
Organ
Number of patients
Kidney
96,922
Liver
15,818
Heart
3,689
Kidney/pancreas
2,031
Lung
1,607
Pancreas
1,178
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LUNG Dr. James Hardy performed the first lung transplant at the University of Mississippi in 1963.31 In 2013, the most common cause for needing a lung transplant was cystic fibrosis in children and chronic obstructive pulmonary disease (COPD) in adults.32,33 Lung transplants can be from deceased or living donors. Adults over age 65 years accounted for the largest growth in adult candidates for transplant in 2011.32 The first living lung transplant occurred in 1990; living donor transplants are not as common as those from deceased donors, and some transplant centers do not perform lung transplants from living donors.34 In a living donor lung transplant, a lung lobe is removed from the donor and transplanted into the recipient. Lung transplants are scored via the Lung Allocation Score (LAS), which is used for patients over age 12 years.35 A change in the LAS in 2005 has led to a decrease in the number of patients who die while on the waiting list, but posttransplant deaths also have increased.36 The increase in a patient’s LAS score right before transplant seems to be the most predictive factor in death after lung transplant; thus, serial measurements are encouraged. An LAS score includes: • wait list urgency measure—the expected number of days a candidate will live without a transplant during an additional year on the waiting list • posttransplant survival measure—the expected number of days a candidate will live during the first year posttransplant • transplant benefit measure—the difference between posttransplant survival and wait list urgency measure • raw allocation score—the difference between transplant benefit measure and wait list urgency measure. The items used to predict survival include, but are not limited to, pulmonary artery pressure, diagnosis, diabetes, forced vital capacity, age, body mass index (BMI), serum creatinine, 6-minute walk distance, mechanical ventilation, and functional status. Grouping classification for transplant is done by diagnosis. As of January 1, 2014, just over 1,600 patients were on the lung transplant waiting list (Table 1).2 PANCREAS William Kelly and Richard Lillehei at the University of Minnesota led the way for both pancreas and pancreas/ intestine transplants.37 They transplanted the first pancreas in 1966, the first pancreas/intestine in 1968, and the first pancreas islet in 1990. The number of pancreas transplants has been decreasing since 2000 and reached a nadir in 2011, the last year for which data are available.38 Outcomes are improving annually for all types of pancreas transplants: simultaneous kidney/pancreas transplant, pancreas alone, and pancreas after kidney transplant. This improvement may be due to better immunosuppression, better surgical technique, or Volume 27 • Number 11 • November 2014
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Transplant in the 21st century
better donor-recipient selection, or a combination of the three.39 The number of patients on the pancreas transplant waiting list is decreasing; 90% of these patients have type 1 diabetes.38 The decreased interest in pancreas transplants may be due to better insulin regimens and increased BMI in patients with diabetes (a stumbling block for listing). Islet cell transplants alone may be offered in a research setting. These are not part of the UNOS data on solid organ transplants. In islet allotransplantation, islet cells from deceased donors are extracted and implanted into the recipient. However, the limited number of appropriate pancreases recovered from deceased donors (1,562 in 2011) meant that few islet cells were available for transplant.38 Not uncommonly, more than one pancreas is needed for each islet cell transplant and the transplant community is hesitant to sacrifice more organs for fewer recipients. Funding poses a major obstacle to islet cell transplants. Currently, islet cell transplants are considered experimental and are not covered by insurance. The National Institutes of Health (NIH) has ongoing studies to work toward FDA approval of islet cell transfers.39 Both Canada and Scandinavia classify islet allotransplantation as therapeutic and not experimental at this time. The waiting list as of January 1, 2014, divides the pancreas waiting list into two sections: pancreas alone (1,178 patients) and kidney/pancreas listing (2,031 patients) (Table 1). INTESTINES The first intestine transplant was by Dr. Thomas Starzl in 1987 on 3-year-old Tabitha Foster.14 Tabitha had been born with short-gut syndrome and had never eaten solid food. Although she only needed intestines and a liver, the surgeons found it easier to transplant the large intestines, stomach, and pancreas along with the small intestine. A splenectomy was also done at the same time. However, Tabitha died 6 months later of Epstein-Barr virus.40 Intestinal transplants are the rarest of organ transplants, with only 46 patients on the transplant list as of January 1, 2014.2 The most common reason for an intestinal transplant is short-gut syndrome followed by functional bowel problems such as Hirschsprung syndrome.41 An intestine transplant can be combined with a liver transplant. Priority for intestine transplants uses the same scoring system as for livers.20 CORNEA The first corneal transplant was performed in 1905 by Eduard Zirm on a farm worker who had burned both eyes while cleaning a chicken coop. A living donor was used, an 11-year-old child who was blind in one eye due to a penetrating injury in the past. The donor eye was enucleated and the cornea was cut into two sections and implanted into the recipient’s eyes. Only one of the corneal transplants survived and the farm laborer had some vision in one eye.42 JAAPA Journal of the American Academy of Physician Assistants
As living donors are uncommon, the concept of deceased donor corneas was broached, and the first eye bank was opened in 1944. Surgical techniques were refined and rejection was controlled. Forty thousand corneal transplants are performed in the United States each year. The leading causes of blindness are cataract, glaucoma, and corneal opacity. Corneal blindness has many causes, ranging from infections to genetic causes. Corneal grafting is used to treat corneal opacity, although lamellar techniques (which remove just the diseased layers of the cornea) are becoming more frequent.43 Lamellar techniques can use full-thickness or partial-thickness corneal grafting (keratoplasty) and have an excellent record of success (80% to 90%).44 Challenges to corneal transplant remain, including a lack of donors. In 2008, the Eye Bank Association of America estimated that about 92,000 corneas were recovered. Of these only 33% were suitable for transplantation. Great strides are being made in developing other techniques to respond to the lack of donors.45 About 20% of patients who undergo keratoplasty reject the implanted corneas, despite antirejection drugs. However, due to advances in cornea transplant and surgical techniques, corneal transplants have allowed many to see who would otherwise remain blind.45 PHARMACOLOGY PROTOCOLS Transplant medication protocols have gone through a sea change over the years. Steroid-driven protocols, which were often the cause of new-onset diabetes, are rare now in the United States.13 Besides induction protocols, most immunosuppressive therapy regimens include a calcineurin inhibitor such as cyclosporine or tacrolimus, and an antimetabolite such as azathioprine, mycophenolate mofetil, sirolimus, or everolimus.13 Each transplant center and each organ has its preferred posttransplant protocol, and a discussion of transplant medications is beyond the scope of this article. However, many PAs will see posttransplant patients in their offices and hospitals, and must remember that: • transplant patients should not be given live vaccines • skin cancer is the most common posttransplant complication; squamous cell cancer is more common than basal cell cancer • all transplant medications have a narrow therapeutic and toxic window, and any interference with the cytochrome P450 system will affect metabolism. Calcium channel blockers, IV protease inhibitors, azole antifungals, antiarrhythmics, antibiotics, antidepressants, antiepileptics, and grapefruit juice can interfere with the cytochrome P450 system and transiently increase or decrease levels of antirejection medications. PAs who practice in an area without a close transplant center may handle a significant amount of primary care for transplant patients, and should be familiar with the www.JAAPA.com
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transplant center’s protocols. Remember that all transplant patients have chronic kidney disease, no matter which organ was transplanted, because transplant medications affect kidney function.46 All medications should be dosed according to the patient’s estimated glomerular filtration rate and not the practice’s standing protocols. DONATION PROTOCOLS The main obstacle to transplant is a lack of donors and not a lack of recipients. In fact, the rate of deceased donors has been flat for 6 years, and the living donor rate has dropped recently (Figure 7). The longest waiting times are for kidneys—8 years or longer in some areas of the country. Part of this is due to the increase in kidney failure, but a second factor is the increased survival of patients with end-stage renal disease, thanks to improved dialysis and better medical management. Studies have shown that minority patients are less likely than nonminority patients to be on a kidney transplant list before starting dialysis.47 Although some of this discrepancy is insurance-driven, the new donation protocols attempt to level the playing field by backdating waiting time to start on the first day of dialysis.7 Two main drives—living donation and presumed consent—have sought to increase donation rates. Living donation is only feasible for kidney, liver, and some lung transplants. However, many of the causes of kidney failure run in families, and the lack of available living donors caused the living donation rate for kidneys to drop in 2012. First-person consent states that if an appropriate deceased donor dies while admitted to a hospital or is dead on arrival, until stated otherwise, the patient will receive care to save the organs for eventual transplant. This also means that if patients have indicated on their driver’s licenses that they are organ donors, family permission is not needed to recover the organs. All 50 states and the District of Columbia have a link between the license donor registration and the organ procurement organizations to allow access of first-person consent in case of death.48
Social media has opened a new outlet for a discussion of living donor transplant.49 Although buying or selling organs is illegal, Facebook recently added a donation button to its social media outreach.50 Various online programs attempt to match patients with organs. Social media outreach remains controversial because of the fear of exploitation, given the high demand for donor organs. One of the most interesting concepts to emerge is a marketing-type outreach recently reported from the United Kingdom (UK).49 Despite the addition of more than 1 million people to the UK donor list in 2011, the donor shortage means that three patients die every day while waiting for a transplant. The UK’s Behavioural Insights Team partnered with the National Health Service and the Driving and Vehicle Licensing Agency to undertake a randomized controlled study to increase donor registrations. When UK drivers went online to renew their license, a screen with one of seven scenarios for donor signup would appear: • the standard request for donation • a “social norm” message (“Every day, millions of people …”) with a photo of a patient • a “social norm” message without a patient photo • a “loss” message (“Three people die each day…”) • a “gain” message (“You could save up to 9 lives…”) • a fairness message (“If you needed an organ transplant, would you have one? If so, please help others”) • No message. The scenario that increased the signup rate was the fairness message. Interestingly, the message with the photo of a patient in need reduced the signup rate. This has changed marketing plans in the UK and should be adopted in the United States. NEW DIRECTIONS Due to the shortage of donor organs, many researchers hope to develop artificial organs. Nonhuman animal cells have been used to treat human conditions (xenotransplant) since the early days of transplant. Although xenotransplantation is common in heart valves, it is not yet used in solid organ transplant.51 Recent advances in 3D printing in biotechnology are showing very interesting results.52 The ability to grow a kidney on a matrix also holds promise for future directions in research.53
FIGURE 7. Deceased and living donors in the United States, 2003-2012
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CONCLUSION Transplants are becoming commonplace and more transplant recipients will be seen in primary care offices. PAs need to have a working knowledge of the types of transplants and general protocols. Patients may mention in passing that a friend, colleague, or neighbor may need a transplant. This Volume 27 • Number 11 • November 2014
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Transplant in the 21st century
can lead to a discussion of donation and the desperate need for more organs. PAs are perfectly placed to dispel rumors and misconceptions about transplants and organ donation. Every day, 17 patients die waiting for a transplant. Each donor saves seven to eight lives, depending on if the liver is split. However, fewer than half of potential donor families are even asked about donation. By understanding organ donation and educating patients, PAs can help fulfill the saying, “To the world you may be one person, but to one person you may be the world.” JAAPA Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of November 2014.
REFERENCES 1. Ellis H. Surgical anniversaries. James Blundell, pioneer of blood transfusion. Br J Hosp Med. 2007;68(8):447. 2. United Network for Organ Sharing. Data. http://www.unos.org/ donation/index.php?topic=data. Accessed July 31, 2014. 3. Organ Procurement and Transplantation Network. Proposal to clarify priority status for prior living organ donors who later require a kidney transplant. http://optn.transplant.hrsa.gov/ publiccomment/pubcommentpropsub_301.pdf. Accessed August 5, 2014. 4. Murray JE, Tilney NL, Wilson RE. Renal transplantation: a twenty-five year experience. Ann Surg. 1976;184(5):565-573. 5. Schatzki S. The first kidney transplantation. Am J Roentgenol. 2003;181(1):190. 6. Chandran S, Vincenti F. Clinical aspects: focusing on key unique organ-specific issues of renal transplantation. Cold Spring Harb Perspect Med. 2014;4(2)1-14. 7. Wiseman A. The risks and rewards in advancing policies to improve kidney transplant rates and outcomes. Nephrology Self-Assessment Program. 2013;(12):309-313. 8. Vella J, Cohen D. Syllabus transplant. Nephrology Self-Assessment Program. 2013;(12):314-321. 9. University of California at San Francisco. Kidney transplantation. http://transplant.surgery.ucsf.edu/conditions—procedures/ kidney-transplantation.aspx. Accessed July 31, 2014. 10. Segev DL, Gentry SE, Warren DS, et al. Kidney paired donation and optimizing the use of live donor organs. JAMA. 2005;293 (15):1883-1890. 11. US Department of Health and Human Services. Organ Procurement and Transplantation Network. KDPI calculator. http:// optn.transplant.hrsa.gov/resources/allocationcalculators. asp?index=80. Accessed July 31, 2014. 12. Malani PN. New law allows organ transplants from deceased HIV-infected donors to HIV-infected recipients. JAMA. 2013;310(23):2492-2493. 13. Gilbert S, Weiner D. National Kidney Foundation’s Primer on Kidney Disease. 6th ed. St. Louis, MO: Elsevier; 2014. 14. Starzl T. The Puzzle People: Memoirs of a Transplant Surgeon. Pittsburgh, PA: University of Pittsburgh Press; 2003. 15. Anantharaju A, Van Thiel DH. Liver Transplantation for Alcoholic Liver Disease. National Institute on Alcohol Abuse and Alcoholism. Position statement. September 29. 2004. http://www. questia.com/library/journal/1P3-732246761/liver-transplantationfor-alcoholic-liver-disease. Accessed August 5, 2014.
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16. Tanne J. Paracetamol causes most liver failure in UK and US. BMJ. 2006;332(7542):628. 17. Reuben A, et al. Acute liver failure (ALF) secondary to drug induced liver injury (DILI): causes & consequences. Hepatology. 2009;50:347A. 18. Harper A, Edwards EB, Mithoefer A, et al. Does clinical or histologic stage make a difference in outcome for patients with HCC receiving liver? Presentation at American Transplant Congress in Seattle, WA, May 18-22, 2013. 19. US Department of Health and Human Services. Organ Procurement and Transplantation Network. About the MELD/PELD calculator. http://optn.transplant.hrsa.gov/resources/ MeldPeldCalculator.asp?index=97. Accessed July 31, 2014. 20. US Department of Health and Human Services. Organ Procurement and Transplantation Network. Policies. http://optn.transplant.hrsa. gov/ContentDocuments/OPTN_Policies.pdf. Accessed July 31, 2014. 21. Moon DB, Lee LG. Liver transplantation. Gut Liver. 2009;3(3): 145-165. 22. Tector AJ, Mangus RS, Chestovich P, et al. Use of extended criteria livers decreases wait time for liver transplantation without adversely impacting posttransplant survival. Ann Surg. 2006;244 (3):439-450. 23. Hoffenberg R. Christiaan Barnard: his first transplants and their impact on concepts of death. BMJ. 2001;323(7327):1478-1480. 24. Jurt U, Delgado D, Malhotra K, et al. Cardiology patient pages. Heart transplant: what to expect. Circulation. 2002;106(14): 1750-1752. 25. US Department of Health and Human Services. Organ Procurement and Transplantation Network. About the heart. http:// optn.transplant.hrsa.gov/organDatasource/about.asp?display= Heart. Accessed July 31, 2014. 26. Acker MA, Pagani FD, Stough WG, et al. Statement regarding the pre and post market assessment of durable, implantable ventricular assist devices in the United States: executive summary. Ann Thorac Surg. 2012;94(6):e163-e168. 27. Cooley DA, Liotta D, Hallman GL. Orthotopic cardiac prosthesis for two-staged cardiac replacement. Am J Cardiol. 1969;24(5):723-730. 28. Frazier OH, Myers TJ, Jarvik RK, et al. Research and development of an implantable, axial-flow left ventricular assist device: the Jarvik 2000 Heart. Ann Thorac Surg. 2001;71(3 suppl): S125-S132. 29. Dipchand A, et al. ECMO as a bridge to pediatric heart transplantation: impact on post-listing and post-transplantation outcomes. Circulation. 2011;124:A16269. 30. Alba AC, Alba LF, Delgado DH, et al. Cost-effectiveness of ventricular assist device therapy as a bridge to transplantation compared with nonbridged cardiac recipients. Circulation. 2013;127(24):2424-2435. 31. Welch C. The world of surgery, 1945-1985: memoirs of one participant. JAMA. 1987;257(6):851. 32. US Department of Health and Human Services. Organ Procurement and Transplantation Network. About the lung. http://optn. transplant.hrsa.gov/organDatasource/about.asp?display=Lung. Accessed July 31, 2014. 33. Liou T, Raman S, Cahill B. Lung transplantation for chronic obstructive pulmonary disease. Transplant Res Risk Manage. 2013;5:1-20. 34. Mohite PN, Popov AF, Yacoub MH, Simon AR. Live related donor lobar lung transplantation recipients surviving well over a decade: still an option in times of advanced donor management. J Cardiothorac Surg. 2013;8:37. 35. Tsuang WM, Vock DM, Finlen Copeland CA, et al. An acute change in lung allocation score and survival after lung transplantation: a cohort study. Ann Intern Med. 2013;158(9): 650-657. www.JAAPA.com
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CME 36. Russo MJ, Iribarne A, Hong KN, et al. High lung allocation score is associated with increased morbidity and mortality following transplantation. Chest. 2010;137(3):651-657. 37. Kelly WD, Lillehei RC, Merkel FK, et al. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery. 1967;61(6):827-837. 38. Kandaswamy R, Stock PG, Skeans MA, et al. OPTN/SRTR 2011 Annual Data Report: pancreas. Am J Transplant. 2013;13(suppl 1):47-72. http://srtr.transplant.hrsa.gov/annual_reports/2011. Accessed August 5, 2014. 39. US Department of Health and Human Services. National Kidney Disease Education Program. http://nkdep.nih.gov. Accessed August 5, 2014. 40. Starzl TE, Rowe MI, Todo S, et al. Transplantation of multiple abdominal viscera. JAMA 1989;261(10):1449-1457. 41. US Department of Health and Human Services. Organ Procurement and Transplantation Network. About the intestine. http:// optn.transplant.hrsa.gov/organDatasource/about.asp?display= Intestine. Accessed July 31, 2014. 42. Crawford AZ, Patel DV, McGhee CNj. A brief history of corneal transplantation: from ancient to modern. Oman J Ophthalmol. 2013;6(suppl 1):S12-S17. 43. National Institutes of Health. National Eye Institute. http:// www.nei.nih.gov. Accessed July 31, 2014. 44. Feilmeier MR, Tabin GC, Williams L, Oliva M. The use of glycerol-preserved corneas in the developing world. Middle East Afr J Ophthalmol. 2010;17(1):38-43.
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45. Griffith M, Jackson WB, Lagali N, et al. Artificial corneas: a regenerative medicine approach. Eye. 2009;23(10):1985-1989. 46. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney disease. Kidney Inter. 2013;(suppl 3):1-150. 47. Malek SK, Keys BJ, Kumar S, et al. Racial and ethnic disparities in kidney transplantation. Transpl Int. 2011;24(5):419-424. 48. US Department of Health and Human Services. State organ donor legislation. http://www.organdonor.gov/legislation_micro. Accessed July 31, 2014. 49. Harper H. UK National Health Service. Applying behavioural insights to organ donation: preliminary results from a randomised controlled trial. https://www.gov.uk/government/uploads/system/ uploads/attachment_data/file/267100/Applying_Behavioural_ Insights_to_Organ_Donation.pdf. Accessed August 5, 2014. 50. Cameron AM, Massie AB, Alexander CE, et al. Social media and organ donor registration: the Facebook effect. Am J Transplant. 2013;13(8):2059-2065. 51. Hammerman MR. Classic and current opinion in embryonic organ transplantation. Curr Opin Organ Transplant. 2014;19 (2):133-139. 52. Schubert C, van Langeveld MC, Donoso LA. Innovations in 3D printing: a 3D overview from optics to organs. Br J Ophthalmol. 2014;98(2):159-161. 53. Song JJ, Guyette JP, Gilpin SE, et al. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med. 2013;19(5):646-651.
Volume 27 • Number 11 • November 2014
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Transplant in the 21st century Kim Zuber, PA-C, DFAAPA; Tricia Howard, PA-C, MHS, DFAAPA; Jane Davis, DNP
ABSTRACT Organ transplantation has enriched and prolonged the lives of many patients who otherwise would have died of organ failure. Many of these advances, which occurred in the later part of the 20th century, are due to improved techniques and pharmacological management. Today, almost every organ can be transplanted. However, donor and recipient criteria can vary widely according to the organ(s) in question. This article reviews the historical changes that have occurred in transplant along with current criteria for donors and recipients, and describes the newest outreach to increase the donor pool. Keywords: transplant, living donation, deceased donor, organ, extended criteria, xenotransplantation
Learning objectives Discuss the historical changes that have occurred in transplant. Identify current criteria for organ donors and recipients. Describe the newest outreach to increase the donor pool.
M
ary Shelley’s 1831 novel, Frankenstein, told the story of a being created from organs and body parts of deceased humans. Modern organ transplantation takes viable organs from deceased or living donors to prolong life for those whose organs have been damaged by disease, trauma, or environmental factors. Shelley was not the first to dream of transplantation; the first recorded blood transfusion, from husband to wife after childbirth, occurred in 1818. The obstetrician, James Kim Zuber practices at Metropolitan Nephrology in Alexandria, Va., and is AAPA Outstanding PA of the Year. Tricia Howard is director of preclinical education at South University in Savannah, Ga., and chair of the National Kidney Foundation’s council of advanced practitioners. Jane Davis is a nurse practitioner at the University of Alabama at Birmingham and a member of the National Kidney Foundation’s board of directors and the American Society of Nephrology’s CME committee. The authors have disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000455644.58683.e8 Copyright © 2014 American Academy of Physician Assistants
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Blundell, transfused 10 women with their husbands’ blood and saved half of them.1 The 20th century was the golden age of transplantation. Kidneys and corneas have led the way and most organs are now transplanted. A notable exception is the brain, which interestingly was the downfall of Shelley’s creation. The 1984 National Organ Transplant Act established a central registry linking donors and potential recipients along with a registry of organ recipients run by the United Network of Organ Sharing (UNOS, http://unos.org). The act also authorized the Organ Procurement and Transplantation Network (OPTN, http://optn.transplant.hrsa.gov/data/ default.asp), which is responsible for the development of US transplant policies and publication of an annual report on the scientific and clinical status of organ transplantation. Much of the data used for this article are available on the UNOS and OPTN websites. We encourage any interested physician assistants (PAs) to log onto these websites for updated information for patients and families. This overview of organ transplantation is to educate PAs on transplant changes for the 21st century; management of the posttransplant patient is beyond the scope of this article. The United States is divided into 11 donation service areas. When an organ is recovered from a deceased donor, it is offered within the donation service area; if no match is found locally, the offer is made nationwide through the UNet system, which electronically links all transplant Volume 27 • Number 11 • November 2014
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Transplant in the 21st century
Key points Organ transplantation has become commonplace, and PAs in primary care should be familiar with types of transplants and protocols so that they can provide care for posttransplant patients. Kidneys are the most frequently transplanted organ and have the longest list waiting time. Medications for transplant patients should be adjusted based on the patient’s estimated glomerular filtration rate. Because of the shortage of donor organs, PAs should encourage patients to consider donation and help dispel misconceptions about organ donation.
hospitals in a secure, real-time environment using the Internet.2 This local, then national, allocation system was originally developed to decrease organ cold ischemic time. Although kidneys continue to be the most frequently transplanted organ with the longest list waiting time, length of waiting time differs in each donation service area (Figure 1). In two instances, this system is bypassed: if there is a perfect match (0 mismatch) of the six human leukocyte antigens (HLAs) or if the recipient is a previous organ donor. All previous organ donors are automatically placed on the top of the transplant list as payback for having previously donated.3 More than 121,000 patients were on transplant waiting lists as of January 1, 2014.2 The vast majority, 96,922, were waiting for a kidney; 15,818 patients were on the liver transplant list (Figure 2). Organs can be recovered from deceased or living donors. Donation after circulatory death (DCD) is also commonly referred to as donation after cardiac death. The newest category, extended criteria donor (ECD), has expanded the resource pool. This is also referred to as extended donor criteria in some publications but we will use the UNOS designation in this article. What defines an ECD organ is specific to the type of transplant. These extended criteria were developed to decrease waste of viable organs with the knowledge that transplant increases survival for patients within any organ system. Each type of donation—deceased donor, living donor, ECD, and DCD—will be discussed by organ and listing protocols will be reviewed. Pediatric donations have their own criteria and are beyond the scope of this article. KIDNEY The kidney is the most commonly transplanted organ in the United States. The first successful kidney transplant occurred
FIGURE 1. Variation in waiting time (months) for patients
receiving a deceased donor kidney in 2011, by donation service area
in Boston on December 23, 1954. Ronald Herrick donated a kidney to his identical twin brother, Richard, who was dying from chronic nephritis. The 5.5-hour surgery was performed by Joseph Murray, MD, a plastic surgeon.4 Richard’s life was saved by the successful surgery, and he later married his recovery room nurse. They had two children, one of whom is a dialysis nurse. Richard died in 1962 after his chronic nephritis returned.5 Kidney transplantation is now the preferred therapeutic modality for patients with kidney disease.6 Nearly 97,000 patients were on the kidney transplant waiting list as of January 1, 2014. Of those, 20% are likely to receive a transplant within a year and about 6% of the patients on the waiting list will die.7 Kidneys have the longest waiting time of any transplanted organ—the average can be as long as 8 years in some regions of the United States—so efforts are under way to increase donations (Figure 3). Donations may be from living or deceased
FIGURE 2. US waiting list additions, 2003-2012
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donors. In 2011, about 5,770 living donor transplants were performed.8 A living kidney donor need not be related to the recipient, but must pass an extensive medical workup. A deceased donor kidney may be recovered from a standard criteria donor (SCD), ECD, DCD, or after brain death. Rates of organ recovery and transplant are different in each donation service area, with some transplant centers more likely to transplant an ECD or DCD organ (Figures 4 and 5). The Uniform Anatomical Gift Act lets a person or family give permission to donate any organs.9 “Domino” transplants can be used to increase the number of transplants for recipients who have a nonmatching donor.10 By using a system that trades kidneys between donors and recipients nationwide, with or without an altruistic donor in the chain, a domino-effect transplant chain can be
created. This lets more patients have living donor transplants, the preferred type of kidney transplant.6 Deceased donor kidneys are assessed based on several factors, including age, ethnicity, history of hypertension or diabetes, HLA antibodies, blood type, and serum creatinine. An ECD kidney is defined by age and/or comorbidities and offered to all recipients with emphasis on the older kidney patient. For kidneys, ECD donation is defined as: • donors over age 60 years • donors ages 50 to 59 years with one or more of the following: stroke as cause of death, history of hypertension, or serum creatinine greater than 1.5 mg/dL at time of death. As of July 2014, the ECD/SCD system has been fully replaced by the kidney donor profile index (KDPI) for all kidney transplants in adults.7 The deceased donor kidney is assigned a KDPI that rates kidney quality from highest to lowest projected longevity. The lower the percentage, the longer the expected life of the kidney.7 This percentage is then used to allocate donor kidneys to recipients based on the recipients’ projected life expectancy as calculated with age, comorbidities, and time on dialysis.11 The recipients with the highest life expectancy receive the higher-survival KDPI-scored donors and vice versa. Providers may access the KDPI at the OPTN website to review factors used to rank deceased donor kidneys. The recent passage of the HOPE (HIV Organ Policy Equity) act lets HIV-positive donors donate to HIV-positive recipients.12 Previously, HIV-positive donors could not donate, even if the recipient was HIV-positive. Patients with hepatitis B and C are listed for kidney transplants and are offered hepatitis-positive organs.6 Recipients who receive kidneys from live donors have longer graft survival than those patients receiving kidneys from deceased donors. The 10-year graft survival rate is 57% for recipients of
FIGURE 4. Organs recovered per donor, by donation status
FIGURE 5. Organs transplanted per donor, by donation status
FIGURE 3. Variation in the use of ECDs for kidney transplant
patients in 2011, by donation service area
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Transplant in the 21st century
living donor kidneys versus 41% for those who received kidneys from deceased donors.8 Acute postoperative complications of kidney transplant (whether living or deceased donor) include urine leaks, ureteral obstruction, vascular complications, and delayed graft function. Urine leak is the most common technical complication following transplant, occurring in 9.3% of patients; delayed graft function is the most common acute complication.6 Delayed graft function, which occurs in 21.3% of posttransplant patients, has several definitions but most often is defined as the use of dialysis within 7 days of transplant. Factors that place the recipient at risk for complications include obesity, diabetes, age over 55 years, male sex, and African American race. Once other causes of kidney dysfunction are excluded, patients should undergo kidney biopsy to assess for acute rejection. Studies have shown that delayed graft function does not have a negative effect on long-term graft survival.6 The ultimate complication is acute rejection. Induction therapy uses strong antirejection medications such as thymogloblin, alemtuzumab, and basiliximab and follows a transplant center–specific protocol peritransplant to decrease T-mediated cell proliferation and organ rejection.13 Despite the use of induction therapy and immunosuppressive agents, acute rejection still can occur; however, the incidence has been decreasing, and fewer than 15% of posttransplant patients develop acute rejection.6 Suspect organ rejection if the patient’s creatinine is rising. A kidney biopsy confirms the diagnosis. Recurrent disease may also occur at any time posttransplant, causing renal graft failure. The most frequent causes of recurrent renal disease are focal segmental glomerulosclerosis (20% to 50% of cases), IgA nephropathy (13% to 53%), lupus nephritis, membranous glomerulonephritis, and diabetic nephropathy.6 However, despite the potential complications, kidney transplantation becomes more successful each year, and can benefit many patients. LIVER In 1963, the first liver transplant was performed by Dr. Thomas Starzl at the University of Colorado. The recipient was Bernie Solis, a 3-year-old dying of biliary atresia.14 Unfortunately, Bernie died in surgery due to portal vein and clotting issues. Dr. Starzl’s first successful liver transplant was later that year, although the patient only lived 22 days posttransplant. The clotting difficulties with the intraoperative external bypass posed the main obstacle to successful and commonplace liver transplants. Alcohol abuse is the most frequent cause of adult liver failure, and a patient who is consuming alcohol cannot be placed on the active transplant waiting list.15 Patients whose alcohol abuse has caused liver failure cannot get a new liver if they are actively drinking. The restrictions depend on the transplant center, but usually patients must abstain from alcohol for 1 to 3 years. JAAPA Journal of the American Academy of Physician Assistants
In the United States, the most common diagnosis for patients on the liver transplant waiting list is hepatitis C, followed by acetaminophen toxicity and medicationinduced liver failure.16,17 Inclusion and priority on the liver transplant list is calculated by Model for End Stage Liver (MELD) score or Pediatric End State Liver (PELD) score; pediatric is defined as a patient under age 12 years.18 The MELD/PELD scores include specific hard data (dialysis two times in the last week, serum creatinine, bilirubin, and international normalized ratio) and are scored from 6 to 40.19 Although dialysis will move a patient up on the liver transplant list with a higher MELD score, few patients in need of a liver transplant are on dialysis. A higher score lets a patient receive a transplant sooner. Recently, controversy has arisen as to whether the sickest patients may be too sick to benefit from a liver transplant. However, OPTN does not plan to change the liver scoring for 2014.20 Liver transplants can be obtained from deceased or living donors. The right lobe of the liver is transplanted from a living donor to the recipient. In a deceased donor, the liver may be split at the time of procurement into two lobes, or the entire liver may be transplanted into one recipient. If the liver is split, the smaller lobe is often transplanted into a child.21 Extended criteria donor livers also are transplanted (Figure 6).22 For liver transplants, ECD is defined as: • donors ages 70 to 80 years • donors older than age 60 years with a significant medical history • donors with a history of high-risk social behaviors • donors with a history of hepatitis B or C exposure. HEART Hearts are the third most often transplanted organ. Dr. Christiaan Barnard performed the first heart transplant
FIGURE 6. Variations in the use of ECDs for patients receiving
liver transplants in 2011, by donation service area www.JAAPA.com
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in 1967 in South Africa. The recipient, Louis Washkansky, died 22 days after the transplant due to pneumonia from immune system oversuppression secondary to antirejection drugs.23 Although heart failure continues to be the main cause of cardiac death, many patients with heart failure are too old or too sick to undergo a heart transplant. The most common causes of listing patients for a heart transplant are cardiomyopathy, congenital heart disease, and ischemic and/or valvular heart disease.24 Heart transplants from deceased donors can be a single organ, or part of a combination heart/lung transplant. Transplants can be single (native heart removed and donor heart placed), heterotopic (native heart is not removed and donor heart placed), or part of a domino heart transplant. A domino heart transplant occurs when a patient needing a lung transplant undergoes a heart/lung transplant. This patient’s native heart is then transplanted into a second recipient in a domino fashion.25 The development of heart devices has revolutionized heart transplants.26,27 Dr. Denton Cooley implanted the first artificial heart at the Texas Heart Institute in 1969; today, vascular assist devices (VADs) developed as bridges to heart transplantation are the more common approach. Willem Johan Kolff (the father of the first dialysis machine) developed the first VADs in the 1970s. The Jarvik 7, developed at the University of Utah in the Kolff laboratory, was the first implantable artificial heart pump designed for long-term use. Intra-aortic balloon pumps (IABPs) and extracorporeal membrane oxygenation (ECMO) are also common bridges to heart transplantation.28,29 Having a VAD or being on ECMO or an IABP will move a patient higher on the transplant list.20 A patient with a VAD (right, left, or bivalve) no longer must wait in the hospital for a heart transplant. Although a heart assist device will classify a patient as a higher priority for transplantation, hospitalization has been dropped from the priority rankings.30 Patients who do not have heart assist devices remain at lower priority on the transplant list.
TABLE 1.
Patients awaiting transplants as of January 1, 2014.
Organ
Number of patients
Kidney
96,922
Liver
15,818
Heart
3,689
Kidney/pancreas
2,031
Lung
1,607
Pancreas
1,178
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LUNG Dr. James Hardy performed the first lung transplant at the University of Mississippi in 1963.31 In 2013, the most common cause for needing a lung transplant was cystic fibrosis in children and chronic obstructive pulmonary disease (COPD) in adults.32,33 Lung transplants can be from deceased or living donors. Adults over age 65 years accounted for the largest growth in adult candidates for transplant in 2011.32 The first living lung transplant occurred in 1990; living donor transplants are not as common as those from deceased donors, and some transplant centers do not perform lung transplants from living donors.34 In a living donor lung transplant, a lung lobe is removed from the donor and transplanted into the recipient. Lung transplants are scored via the Lung Allocation Score (LAS), which is used for patients over age 12 years.35 A change in the LAS in 2005 has led to a decrease in the number of patients who die while on the waiting list, but posttransplant deaths also have increased.36 The increase in a patient’s LAS score right before transplant seems to be the most predictive factor in death after lung transplant; thus, serial measurements are encouraged. An LAS score includes: • wait list urgency measure—the expected number of days a candidate will live without a transplant during an additional year on the waiting list • posttransplant survival measure—the expected number of days a candidate will live during the first year posttransplant • transplant benefit measure—the difference between posttransplant survival and wait list urgency measure • raw allocation score—the difference between transplant benefit measure and wait list urgency measure. The items used to predict survival include, but are not limited to, pulmonary artery pressure, diagnosis, diabetes, forced vital capacity, age, body mass index (BMI), serum creatinine, 6-minute walk distance, mechanical ventilation, and functional status. Grouping classification for transplant is done by diagnosis. As of January 1, 2014, just over 1,600 patients were on the lung transplant waiting list (Table 1).2 PANCREAS William Kelly and Richard Lillehei at the University of Minnesota led the way for both pancreas and pancreas/ intestine transplants.37 They transplanted the first pancreas in 1966, the first pancreas/intestine in 1968, and the first pancreas islet in 1990. The number of pancreas transplants has been decreasing since 2000 and reached a nadir in 2011, the last year for which data are available.38 Outcomes are improving annually for all types of pancreas transplants: simultaneous kidney/pancreas transplant, pancreas alone, and pancreas after kidney transplant. This improvement may be due to better immunosuppression, better surgical technique, or Volume 27 • Number 11 • November 2014
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better donor-recipient selection, or a combination of the three.39 The number of patients on the pancreas transplant waiting list is decreasing; 90% of these patients have type 1 diabetes.38 The decreased interest in pancreas transplants may be due to better insulin regimens and increased BMI in patients with diabetes (a stumbling block for listing). Islet cell transplants alone may be offered in a research setting. These are not part of the UNOS data on solid organ transplants. In islet allotransplantation, islet cells from deceased donors are extracted and implanted into the recipient. However, the limited number of appropriate pancreases recovered from deceased donors (1,562 in 2011) meant that few islet cells were available for transplant.38 Not uncommonly, more than one pancreas is needed for each islet cell transplant and the transplant community is hesitant to sacrifice more organs for fewer recipients. Funding poses a major obstacle to islet cell transplants. Currently, islet cell transplants are considered experimental and are not covered by insurance. The National Institutes of Health (NIH) has ongoing studies to work toward FDA approval of islet cell transfers.39 Both Canada and Scandinavia classify islet allotransplantation as therapeutic and not experimental at this time. The waiting list as of January 1, 2014, divides the pancreas waiting list into two sections: pancreas alone (1,178 patients) and kidney/pancreas listing (2,031 patients) (Table 1). INTESTINES The first intestine transplant was by Dr. Thomas Starzl in 1987 on 3-year-old Tabitha Foster.14 Tabitha had been born with short-gut syndrome and had never eaten solid food. Although she only needed intestines and a liver, the surgeons found it easier to transplant the large intestines, stomach, and pancreas along with the small intestine. A splenectomy was also done at the same time. However, Tabitha died 6 months later of Epstein-Barr virus.40 Intestinal transplants are the rarest of organ transplants, with only 46 patients on the transplant list as of January 1, 2014.2 The most common reason for an intestinal transplant is short-gut syndrome followed by functional bowel problems such as Hirschsprung syndrome.41 An intestine transplant can be combined with a liver transplant. Priority for intestine transplants uses the same scoring system as for livers.20 CORNEA The first corneal transplant was performed in 1905 by Eduard Zirm on a farm worker who had burned both eyes while cleaning a chicken coop. A living donor was used, an 11-year-old child who was blind in one eye due to a penetrating injury in the past. The donor eye was enucleated and the cornea was cut into two sections and implanted into the recipient’s eyes. Only one of the corneal transplants survived and the farm laborer had some vision in one eye.42 JAAPA Journal of the American Academy of Physician Assistants
As living donors are uncommon, the concept of deceased donor corneas was broached, and the first eye bank was opened in 1944. Surgical techniques were refined and rejection was controlled. Forty thousand corneal transplants are performed in the United States each year. The leading causes of blindness are cataract, glaucoma, and corneal opacity. Corneal blindness has many causes, ranging from infections to genetic causes. Corneal grafting is used to treat corneal opacity, although lamellar techniques (which remove just the diseased layers of the cornea) are becoming more frequent.43 Lamellar techniques can use full-thickness or partial-thickness corneal grafting (keratoplasty) and have an excellent record of success (80% to 90%).44 Challenges to corneal transplant remain, including a lack of donors. In 2008, the Eye Bank Association of America estimated that about 92,000 corneas were recovered. Of these only 33% were suitable for transplantation. Great strides are being made in developing other techniques to respond to the lack of donors.45 About 20% of patients who undergo keratoplasty reject the implanted corneas, despite antirejection drugs. However, due to advances in cornea transplant and surgical techniques, corneal transplants have allowed many to see who would otherwise remain blind.45 PHARMACOLOGY PROTOCOLS Transplant medication protocols have gone through a sea change over the years. Steroid-driven protocols, which were often the cause of new-onset diabetes, are rare now in the United States.13 Besides induction protocols, most immunosuppressive therapy regimens include a calcineurin inhibitor such as cyclosporine or tacrolimus, and an antimetabolite such as azathioprine, mycophenolate mofetil, sirolimus, or everolimus.13 Each transplant center and each organ has its preferred posttransplant protocol, and a discussion of transplant medications is beyond the scope of this article. However, many PAs will see posttransplant patients in their offices and hospitals, and must remember that: • transplant patients should not be given live vaccines • skin cancer is the most common posttransplant complication; squamous cell cancer is more common than basal cell cancer • all transplant medications have a narrow therapeutic and toxic window, and any interference with the cytochrome P450 system will affect metabolism. Calcium channel blockers, IV protease inhibitors, azole antifungals, antiarrhythmics, antibiotics, antidepressants, antiepileptics, and grapefruit juice can interfere with the cytochrome P450 system and transiently increase or decrease levels of antirejection medications. PAs who practice in an area without a close transplant center may handle a significant amount of primary care for transplant patients, and should be familiar with the www.JAAPA.com
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transplant center’s protocols. Remember that all transplant patients have chronic kidney disease, no matter which organ was transplanted, because transplant medications affect kidney function.46 All medications should be dosed according to the patient’s estimated glomerular filtration rate and not the practice’s standing protocols. DONATION PROTOCOLS The main obstacle to transplant is a lack of donors and not a lack of recipients. In fact, the rate of deceased donors has been flat for 6 years, and the living donor rate has dropped recently (Figure 7). The longest waiting times are for kidneys—8 years or longer in some areas of the country. Part of this is due to the increase in kidney failure, but a second factor is the increased survival of patients with end-stage renal disease, thanks to improved dialysis and better medical management. Studies have shown that minority patients are less likely than nonminority patients to be on a kidney transplant list before starting dialysis.47 Although some of this discrepancy is insurance-driven, the new donation protocols attempt to level the playing field by backdating waiting time to start on the first day of dialysis.7 Two main drives—living donation and presumed consent—have sought to increase donation rates. Living donation is only feasible for kidney, liver, and some lung transplants. However, many of the causes of kidney failure run in families, and the lack of available living donors caused the living donation rate for kidneys to drop in 2012. First-person consent states that if an appropriate deceased donor dies while admitted to a hospital or is dead on arrival, until stated otherwise, the patient will receive care to save the organs for eventual transplant. This also means that if patients have indicated on their driver’s licenses that they are organ donors, family permission is not needed to recover the organs. All 50 states and the District of Columbia have a link between the license donor registration and the organ procurement organizations to allow access of first-person consent in case of death.48
Social media has opened a new outlet for a discussion of living donor transplant.49 Although buying or selling organs is illegal, Facebook recently added a donation button to its social media outreach.50 Various online programs attempt to match patients with organs. Social media outreach remains controversial because of the fear of exploitation, given the high demand for donor organs. One of the most interesting concepts to emerge is a marketing-type outreach recently reported from the United Kingdom (UK).49 Despite the addition of more than 1 million people to the UK donor list in 2011, the donor shortage means that three patients die every day while waiting for a transplant. The UK’s Behavioural Insights Team partnered with the National Health Service and the Driving and Vehicle Licensing Agency to undertake a randomized controlled study to increase donor registrations. When UK drivers went online to renew their license, a screen with one of seven scenarios for donor signup would appear: • the standard request for donation • a “social norm” message (“Every day, millions of people …”) with a photo of a patient • a “social norm” message without a patient photo • a “loss” message (“Three people die each day…”) • a “gain” message (“You could save up to 9 lives…”) • a fairness message (“If you needed an organ transplant, would you have one? If so, please help others”) • No message. The scenario that increased the signup rate was the fairness message. Interestingly, the message with the photo of a patient in need reduced the signup rate. This has changed marketing plans in the UK and should be adopted in the United States. NEW DIRECTIONS Due to the shortage of donor organs, many researchers hope to develop artificial organs. Nonhuman animal cells have been used to treat human conditions (xenotransplant) since the early days of transplant. Although xenotransplantation is common in heart valves, it is not yet used in solid organ transplant.51 Recent advances in 3D printing in biotechnology are showing very interesting results.52 The ability to grow a kidney on a matrix also holds promise for future directions in research.53
FIGURE 7. Deceased and living donors in the United States, 2003-2012
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CONCLUSION Transplants are becoming commonplace and more transplant recipients will be seen in primary care offices. PAs need to have a working knowledge of the types of transplants and general protocols. Patients may mention in passing that a friend, colleague, or neighbor may need a transplant. This Volume 27 • Number 11 • November 2014
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Transplant in the 21st century
can lead to a discussion of donation and the desperate need for more organs. PAs are perfectly placed to dispel rumors and misconceptions about transplants and organ donation. Every day, 17 patients die waiting for a transplant. Each donor saves seven to eight lives, depending on if the liver is split. However, fewer than half of potential donor families are even asked about donation. By understanding organ donation and educating patients, PAs can help fulfill the saying, “To the world you may be one person, but to one person you may be the world.” JAAPA Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of November 2014.
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JAAPA Journal of the American Academy of Physician Assistants
16. Tanne J. Paracetamol causes most liver failure in UK and US. BMJ. 2006;332(7542):628. 17. Reuben A, et al. Acute liver failure (ALF) secondary to drug induced liver injury (DILI): causes & consequences. Hepatology. 2009;50:347A. 18. Harper A, Edwards EB, Mithoefer A, et al. Does clinical or histologic stage make a difference in outcome for patients with HCC receiving liver? Presentation at American Transplant Congress in Seattle, WA, May 18-22, 2013. 19. US Department of Health and Human Services. Organ Procurement and Transplantation Network. About the MELD/PELD calculator. http://optn.transplant.hrsa.gov/resources/ MeldPeldCalculator.asp?index=97. Accessed July 31, 2014. 20. US Department of Health and Human Services. Organ Procurement and Transplantation Network. Policies. http://optn.transplant.hrsa. gov/ContentDocuments/OPTN_Policies.pdf. Accessed July 31, 2014. 21. Moon DB, Lee LG. Liver transplantation. Gut Liver. 2009;3(3): 145-165. 22. Tector AJ, Mangus RS, Chestovich P, et al. Use of extended criteria livers decreases wait time for liver transplantation without adversely impacting posttransplant survival. Ann Surg. 2006;244 (3):439-450. 23. Hoffenberg R. Christiaan Barnard: his first transplants and their impact on concepts of death. BMJ. 2001;323(7327):1478-1480. 24. Jurt U, Delgado D, Malhotra K, et al. Cardiology patient pages. Heart transplant: what to expect. Circulation. 2002;106(14): 1750-1752. 25. US Department of Health and Human Services. Organ Procurement and Transplantation Network. About the heart. http:// optn.transplant.hrsa.gov/organDatasource/about.asp?display= Heart. Accessed July 31, 2014. 26. Acker MA, Pagani FD, Stough WG, et al. Statement regarding the pre and post market assessment of durable, implantable ventricular assist devices in the United States: executive summary. Ann Thorac Surg. 2012;94(6):e163-e168. 27. Cooley DA, Liotta D, Hallman GL. Orthotopic cardiac prosthesis for two-staged cardiac replacement. Am J Cardiol. 1969;24(5):723-730. 28. Frazier OH, Myers TJ, Jarvik RK, et al. Research and development of an implantable, axial-flow left ventricular assist device: the Jarvik 2000 Heart. Ann Thorac Surg. 2001;71(3 suppl): S125-S132. 29. Dipchand A, et al. ECMO as a bridge to pediatric heart transplantation: impact on post-listing and post-transplantation outcomes. Circulation. 2011;124:A16269. 30. Alba AC, Alba LF, Delgado DH, et al. Cost-effectiveness of ventricular assist device therapy as a bridge to transplantation compared with nonbridged cardiac recipients. Circulation. 2013;127(24):2424-2435. 31. Welch C. The world of surgery, 1945-1985: memoirs of one participant. JAMA. 1987;257(6):851. 32. US Department of Health and Human Services. Organ Procurement and Transplantation Network. About the lung. http://optn. transplant.hrsa.gov/organDatasource/about.asp?display=Lung. Accessed July 31, 2014. 33. Liou T, Raman S, Cahill B. Lung transplantation for chronic obstructive pulmonary disease. Transplant Res Risk Manage. 2013;5:1-20. 34. Mohite PN, Popov AF, Yacoub MH, Simon AR. Live related donor lobar lung transplantation recipients surviving well over a decade: still an option in times of advanced donor management. J Cardiothorac Surg. 2013;8:37. 35. Tsuang WM, Vock DM, Finlen Copeland CA, et al. An acute change in lung allocation score and survival after lung transplantation: a cohort study. Ann Intern Med. 2013;158(9): 650-657. www.JAAPA.com
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CME 36. Russo MJ, Iribarne A, Hong KN, et al. High lung allocation score is associated with increased morbidity and mortality following transplantation. Chest. 2010;137(3):651-657. 37. Kelly WD, Lillehei RC, Merkel FK, et al. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery. 1967;61(6):827-837. 38. Kandaswamy R, Stock PG, Skeans MA, et al. OPTN/SRTR 2011 Annual Data Report: pancreas. Am J Transplant. 2013;13(suppl 1):47-72. http://srtr.transplant.hrsa.gov/annual_reports/2011. Accessed August 5, 2014. 39. US Department of Health and Human Services. National Kidney Disease Education Program. http://nkdep.nih.gov. Accessed August 5, 2014. 40. Starzl TE, Rowe MI, Todo S, et al. Transplantation of multiple abdominal viscera. JAMA 1989;261(10):1449-1457. 41. US Department of Health and Human Services. Organ Procurement and Transplantation Network. About the intestine. http:// optn.transplant.hrsa.gov/organDatasource/about.asp?display= Intestine. Accessed July 31, 2014. 42. Crawford AZ, Patel DV, McGhee CNj. A brief history of corneal transplantation: from ancient to modern. Oman J Ophthalmol. 2013;6(suppl 1):S12-S17. 43. National Institutes of Health. National Eye Institute. http:// www.nei.nih.gov. Accessed July 31, 2014. 44. Feilmeier MR, Tabin GC, Williams L, Oliva M. The use of glycerol-preserved corneas in the developing world. Middle East Afr J Ophthalmol. 2010;17(1):38-43.
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45. Griffith M, Jackson WB, Lagali N, et al. Artificial corneas: a regenerative medicine approach. Eye. 2009;23(10):1985-1989. 46. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney disease. Kidney Inter. 2013;(suppl 3):1-150. 47. Malek SK, Keys BJ, Kumar S, et al. Racial and ethnic disparities in kidney transplantation. Transpl Int. 2011;24(5):419-424. 48. US Department of Health and Human Services. State organ donor legislation. http://www.organdonor.gov/legislation_micro. Accessed July 31, 2014. 49. Harper H. UK National Health Service. Applying behavioural insights to organ donation: preliminary results from a randomised controlled trial. https://www.gov.uk/government/uploads/system/ uploads/attachment_data/file/267100/Applying_Behavioural_ Insights_to_Organ_Donation.pdf. Accessed August 5, 2014. 50. Cameron AM, Massie AB, Alexander CE, et al. Social media and organ donor registration: the Facebook effect. Am J Transplant. 2013;13(8):2059-2065. 51. Hammerman MR. Classic and current opinion in embryonic organ transplantation. Curr Opin Organ Transplant. 2014;19 (2):133-139. 52. Schubert C, van Langeveld MC, Donoso LA. Innovations in 3D printing: a 3D overview from optics to organs. Br J Ophthalmol. 2014;98(2):159-161. 53. Song JJ, Guyette JP, Gilpin SE, et al. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med. 2013;19(5):646-651.
Volume 27 • Number 11 • November 2014
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